Process for the n-alkylation of acyl anilides halogen substituted in the nucleus



United States Patent 3,178,473 PROCESS FOR THE N-ALKYLATION 0F ACYLANILIDES HALOGEN SUBSTITUTED JN THE NUCLEUS Hugo Holtermann, Hovik,Baerum, Leif Gunnar Haugen, Grefsen, Oslo, Vegard Nordal, Smedstad,Oslo, and Johan Lyder Haavaldsen, Oslo, Norway, .assignors to Nyegaard&'Co. A/S, Oslo, Norway No Drawing. Filed Mar. 2, 1962, Ser. No. 176,894

Claims. (Cl. 260--519) This invention relates to the preparation ofcompounds of the general Formulas A and B wherein R is a substituted orunsubstituted alkyl group, such as for example methyl, propyl,carboxymethyl, carbalkoxymethyl or hydroxyethyl, X is hydrogen or iodineatoms at least two of them being iodine and, Y designates hydrogen or adesired substituent such as a carboxyl, carbalkoxyl, amino, acylamino orthe group and wherein Z designates the residue of a substituted orunsubstituted aliphatic or aromatic carboxylic acid, for example anacetyl group.

"Particularly the invention relates to those compounds of the abovegeneral formula in which X is iodine and where R, Y and Z have themeanings given above.

The practical importance of the invention is apparent from the fact thatnew and valuable compounds can be prepared by the process, especiallyX-ray'contrast agents, in which case the compounds which are acids maybe used in the form of their non-toxic salts, and intermediates in theirproduction. Thus, for instance, the new X-ray agentN-methyl-3,5-diacetamido-2,4,-triiodobenzoic acid (I) is made easilyavailable by means of this invention, and also methylN-methyl-3,5-diacetarnido-2,4,6-triiodobenzoate (II and 3 (Nmethylacetamido) 5 amino- 2,4,6-triiodobenzoic acid (III), the lattertwo compounds (II and III) being important intermediates in processesfor the production of (I) The novelty and characteristic inventivefeature of the process is a simple and eificient method of makingcompounds of the above general Formula A or B whereby theN-substituted-acylamido group (RAIL-z of the above general Formula A orB is formed.

It will be seen that the compounds of the above general Formula A arederivatives of N-alkyl-acylanilides, thus, Compound I for example, is a2,4,6-triiodo-3-acetamido-5-carboxy-N-methylacetanilide.

The general methods of organic chemistry for making N-alkylacylanilidesare the following, as exemplified by N-methylacetanilide:

(1) Aniline is methylated by means of a methylating agent (dimethylsulphate, methyl p-toluene sulphonate,

3,i?8,473 Patented Apr. 13, 1965 "Ice (2) Aniline is reacted withp-toluenesulphonic acid chloride (or benzene-sulphonic acid chloride),the p-toluenesulphonanilide formed is methylated, the N- methylatedreaction product hydrolysed under drastic conditions (strong mineralacid, heat) yielding 'N-methylaniline, which is finally acetylated:

IYIH: Imam-@011,

(3) Acetanilide is converted to the sodium salt by heating it withpowdered metallic sodium in a high boiling inert solvent, for exampleXylene, followed -by treatment of the sodium salt with a methylatingagent (for example methyl iodide) AclTIH AclTT-Na ITTHCH; AeIIT-CH;

A CIIL- 0 H3 It is true that methylaniline according to procedure 1above can technically be separated from the other reaction products andfrom unreacted aniline by fractional distillation or by fractionalcrystallization of the hydrochlorides, but these are special separationprocedures not generally applicable and are in any case irrelevant forthe present analysis.

The present invention is characterised by the discovery that theN-substituted acylanilides of the above general Formulas A or B areprepared by N-substitution in alkaline aqueous solution (for examplesodium hydroxide solution), alkaline aqueous-organic solution (forexample alkaline aqueous methanolic solution) or organic solution in thepresence of a base (for example ethoxide in ethanol) of the acylanilidesof the general Formula C according to the general reaction:

HIYT- Z RIFT Z X X X X Y Y Y Y 3 bromoacetic acid, ethyl bromoacetate,ethylenebromohydrin, etc.)

We have thus found that while acylanilides in general are not alkylatedin solution in the presence of alkali or sodiumalkoxides, this is thecase when two or more halogens are introduced into the ortho and parapositions relative to the nitrogen atom of the anilide.

This may appear the more surprising when one con siders the sterichindrance known to operate in the neig boring positions of aromaticbound halogens and which is quite formidable in the case of iodine. Itis furthermore noteworthy that reaction mechanism studies indicate thatthe alkylation reaction is proceeded by enolization and ionization ofthe acylamido group of the anilide to be alkylated, in spite of the workof Neudert and Ropke (Chem. Ber., 87, 659-667 (1954)) who found noindication of a tendency of enolisation or dissociation of the acetamidogroup in their ultraviolet absorption studies on adipoyl bis(2,4,6-triiodo-3-carboXy-anilide) (IV) which is easily methylated inaqueous alkali according to the invention to the N,N-dimethyl derivative(V) I I I I -NH 0 (013940 OHN (IJO H 11 I I I I NC 0 (011,) 0 ON I H H IFurthermore we have found that the general method (method 3 above) ofalkylating anilides by successive treatment with metallic sodium and analkylating agent is not generally applicable on the polyhalo-anilides ofthe invention (general Formula C above). It has thus for instance notbeen possible in our hands to N-alkylate methyl3,5-diacetamido-2,4,6-triiodobenzoate by successive treatment withmetallic sodium and methyl iodide (or dimethyl sulphate) in boilingxylene (or dioXan) although the alkylation proceeds rapidly at roomtemperature and below in aqueous alkali.

We have also found that an ordinary alkylation (according to method 1above) of amino-nitrogen prior to the introduction of the acyl group ofthe compounds of the general Formula C is not generally applicable andhas failed completely in our hands for example in the case of3,S-diamino-2,4,6-triiodobenzoic acid which could not be N-methylated bymeans of methyl iodide or dimethyl sulphate. This is taken advantage ofin the present invention according to which compounds of the generalFormula C in which one Y is an amino group and the other Y is anacetamido group can be alkylated exclusively on the amide-nitrogen as inthe following reaction:

(I) 0 2H (I: 0111 I I I H N- -NHAc H N -NAc (III) where no trace isfound of a derivative carrying a methyl group on the amino nitrogen, andwhere the yield of the desired Compound III is nearly quantitative. Thisreaction is of great importance because the intermediate (III) caneasily by acetylation be converted to the valuable N-methyl-3,5-diacetamido 2,4,6 triiodobenzoic acid mentioned above.

Method 2 above is not generally feasable because of the extraordinaryresistance to hydrolysis of polyhalogen substituted anilides, and wouldof obvious reasons constitute an unnecessary and laborious complication.

The present invention therefore is founded on the discovery that acylanilides of the above general Formula C (1) Can be N-alkylated inalkaline aqueous or organic solution as easily as sulphonanilides,contrary to other ordinary acylanilides and that (2) The ordinary methodof N-alkylation of anilides is not generally applicable to the compoundsof the invention.

As to the interpretation of the general Formulae A and C it should bestated clearly that they are intended to cover also compounds whichcontain two or more acyl anilido groups in the same or in differentaromatic nuclei, thus the following compounds and reactions fall withinthis invention:

I I I I AcHN NHAc AcHN NAc I I Hz AcN NAc is, I in.

I I I NHOO (CH2)4CONH ([JOZH 00111 I I I I NCO (CH2)4CON I CH (1H I Ithas furthermore been found that certain compounds of the general FormulaC of the invention can be further alkylated when suitable groups (forexample carboxyl groups) are present as substituents, and that in suchcases it is usually possible to lead the reaction so as to give the oneor the other reaction product. It is thus possible according to theinvention to methylate 3,5-diacetamido- 2,4,6-triiodobenzoic acid toeither the N-monomethyl acid, the N,N-dimethyl acid or theN,N-dimethyl-methyl ester as illustrated by the following formula:

(iJOzII (IJOQH I I I I AcHN- NHAc AcHN- NAc I I Ha (IJO H 00 011 I I I IAcN NAc .AcN- NAc H3 I H5 (EH3 I H3 and while this reaction sequencetakes place in aqueous media, N-alkylation taking place more rapidlythan esterification, the following sequence is predominant in nonaqueousmedia, esterification taking place more rapidly TABLE ICI1ti1111ed thanN-methylation: ion: 00,11 HOOC-(CH hCOlFI-R (10211 2 3 I I I I I I 5 I II I NCO(CH;)4CON AeHN- NHAc AcHN- NHAe I CH3 I I I I R=H, CH3 R=CH3,CQH5, 03H? ooze (|302CH3 $0211 F I I I I I I I AoHN- -NAc ACN NAO I i bI R I R I H H 1 H3 In some such cases it may be an advantage to carrythe reaction to the completely N-methylated ester stage and I I I I thenconvert the N-methylated ester to the acid if the latter compound isdesired. AcylHN NAcyI 1 IL I It has furthermore been found that in thecases Where the N-methylated acylanilides of the invention carry anHZCOOH iodine atom in both ortho positions to the acylamido group a newtype of isomerisrn occurs which is due to re- GO H 003E I strictedrotation of the acyl group around the axis .con- I I I necting thecarbonyl carbon-atom with the nitrogen atom, making twothermodynamically preferred orientations of A 1 A the acyl grouppossible, one in which the carbonyl of the c} Cy c N Ac I J; J, acylgroup points inwards towards the aromatic nucleus R I R H010 I HICOflH(endo form) and another in which it points outwards away from thearomatic nucleus (exo form), the two forms adopting theirthermodynamical equilibrium rapidly above 70 C.

The process of the invention is very simple and is carried out in thefollowing Way. The acyl-polyhalo-anilide is dissolved in aqueous alkalieventually by the help of I 1110331011 an organic solvent (for exampleacetone, methanol, di- C'H CH OH oXan etc.), or it is dissolved in anorganic solvent towhich is added strong alkali or an alkali alkoxide orsome other 40 TABLE II suitable base, and the alkylating agent (forexample di- AcylNgflaqozR methyl sulphate, methyl p-toluene sulphonate,propyl I I I I iodide etc.) is added preferably in portionswithstirring, I I I I I I 1 dissolved in some solvent which will give a'homogeneous solution. Stirring and cooling are usually advantageously II I I vA N NAG employed in the case of the very reactive alkylatingagents.

The compounds of Table II below are examples-of compounds which can beprepared according to the invention, those of Table I comprise thosewhich have actually been 01120013 01129013 prepared. TABLE I NC 0 (CH -GO N AeylN (CH Il-N Aeyl I CH -ITI-A0 Join (303R I I 3 I I I i I I r r rI I I I I 1 -NAO HZN --NAc R =H, alkyl 1 1 Jam 1 on,

I I I I I r .I I

AcHN NAe AcN -NAc R =alkyl I R =11, alkyl R =alkyl I I I I r r 'I r I IR =allq71 R =H, alkyl TABLE IIContinued C R 0 OgR I I I I lTT-Acyl HzN--N-Acyl I R I R R =H, alkyl R =H, alkyl R =alkyl R =alky1 O 0 R 0 0 R II I I HzN -IIIC 0 (CH2) 4C ON -NH, OH; (EH; I R=H, CH;

I I I Acyl HN lTT-Acyl .AcHN NAc I R I 6111 C 0 2R R=H, alkyl R, R=H,alkyl R: alkyl I I I I AcHN -NAc Acyl-N- N-Aeyl I HzCHgOH R I R 11:13 1k1 R=H alk l a y R'=R'"=ik 1 0 0 B C 0 R I I I I AeN- NAe AcN NAc J; IHgCOgR' l I HgCHzOH HzCOgR' HzCHzOH R, R=alkyl R=alky1 EXAMPLE 1N-methyl-Z,4,6-triiod0acetanilide Triiodoacetanilide (3.9 mmol., 2 g.)was suspended in 20 ml. of ethanol and brought into solution by means of2 ml. of N methanolic sodium hydroxide. Dimethyl sulphate (6.4 mmol.,0.6 ml.) was added while stirring and placed on a water bath at 60 C.After about minutes N-methyl-2,4,6-triiodoacetanilide crystallised andwas filtered after 12 hours standing and washed on the filter with 5 ml.of ethanol. The pistol dried product (0.6 g., 78% of theory) melted at183l90 C. (Mixture of the acetexo and acetendo forms.)

EXAMPLE 2 N-mezhyl-3-acclamid0-2,4,6-trii0d0benzoic acid3-acetamido-2,4,6-triiodobenzoic acid (0.147 mol., 82 g.) was dissolvedin a mixture of water (80 ml.) and 5 N sodium hydroxide (3.7 eqv., 110ml.). The solution was cooled to about 15 C. and dimethyl sulphate (1.2eqv.), dissolved in acetone (17 ml.) was added with stirring at arelatively slow rate. After 45 minutes stirring the N-methyl-3-acetamido-2,4,6-triiodobenzoic acid was precipitated byaddition of hydrohcloric acid (1:1) to pH about 0.5. The moist acid,containing the exo and endo isomers in about equal proportions wasdissolved as their ammonium salts in about 400 ml. of water and thesolution kept in boiling water bath for about 45 minutes in order toconvert the thermodynamically less stable isomer (endo compound) intothe more stable (exo compound), whereafter the solution was treated withactive carbon, filtered, cooled and precipitated by means ofhydrochloric acid 7 0 (1:1), stirred for about 1 hour, filtered, washedwith water and dried. Exo-N-methyl-3-acetamido-2,4,6-triiodobenzoic acidwas obtained in 94% yield (79 g.).

EXAMPLE 3 5-amino-3-(N-methylacetamido)-2,4,6-triiod0benz0ic acid Methyl5 -amino-3 (N-mcthylacetamido) -2,4,6- triiodobenzoate3-acetamido-5-amino-2,4,6-triiodobenzoic acid (2 g.) was suspended inwater (2 ml.) and dissolved by adding 7.8 m1. of 5 N potassiumhydroxide. Dimethyl sulphate (1.8 ml.) dissolved in acetone (l.8 ml.)was added in portions with stirring at 50 C. The insoluble methyl 5-.amino 3 (N-methylacetamido) 2,4,6-triiodobenzoate which precipitatedwas filtered, washed with dilute acetic acid and with water and dried(2.0 g.).

EXAMPLE 5 Methyl N-methyl-3,5-diacctamid0-2,4,6-trii0dobenzoate Methyl3,S-diacetamido-2,4,6-triiodobenzoate (50 g; 0.08 mol.) was suspended inwater (150 ml.) and dissolved by adding 5 N potassium hydroxide (38 ml.;2.4 eqv.). Acetone (5 ml.) was added with stirring followed by dimethylsulphate (8 ml.; 1.05 eqv.) dissolved in acetone (10 ml.) slowly atabout 15 C. After 1% hours insoluble methylN,N'-dimethyl-3,5-diacetamido-2,4,6- triiodobenzoate (2.9 g.) wasseparated by filtration. The filtrate was acidified by means ofconcentrated hydrochloric acid (about 20 ml.) and the precipitatedmaterial filtered, Washed with water, redissolved in strong alkali to aconcentration of about 10% ester, filtered from a small amount ofN,N-dimethyl-mcthylester, the filtrate reacidified and the practicallypure methyl N-methyl-3,5-diacetamido-Z,4,6-triiodobenzoate filtered,washed with water and dried.

EXAMPLE 6A N-methyl-3,5-diacetamido-2,4,6-triiod0benzoic acid 502.4 g.(0.8 mol.) of methyl 3,5-diacetamido-2,4,6-triiodobenzoate is dissolvedin 800 ml. 5 N aqueous potassium hydroxide (4 mol.) by mechanicalagitation and gentle heating. All material dissolves and the solution iscooled to room temperature whereafter 1600 ml. of molar methanolicmethylsulphuric acid is added with stirring. The mixture is heated onboiling water bath for 10 minutes under reflux cooling. Then the heatingcontinues on the boiling water bath with descending condenser. Afterabout 2 hours about 1420 ml. has distilled over at 72- 82". Some solidsubstance has precipitated, and a further 200 ml. (1 mol.) 5 N potassiumhydroxide and 22 g. of solid (85%) potassium hydroxide are added, afterwhich heating on boiling water bath continues with descending cooler.After minutes a sample of the mixture gives, after addition of glacialacetic acid to pH about 4.5, no longer any precipitate. Altogether about1560 ml. distillate has been collected.

The heating is suspended and to the darkbrown mixture is added 500 ml.of water. After cooling to room temperature, the precipitated substanceis filtered by suction on a glass filter and washed with 250 ml. ofwater.

The two filtrates are combined and filtered. To this clear, brown,filtered liquid (1920 ml.) is added with mechanical stirring 970 ml. ofdilute hydrochloric acid (1 :2) to pH about 4. After standing over nightthe solution is filtered from a voluminous, chocolate-brown precipitate,which is washed with 400 ml. water. Filtrate and washings .are combinedand 70 g. of carbon (index 35) added, heated to boiling and filtered.The filtrate is washed with about 1000 ml. of water and the twofiltrates combined. To the tea-coloured solution is added about 2150 ml.dilute hydrochloric acid (1:2) with mechanical stirring to pH 10.5.After agitation over night it is filtered on a sintered plate (G4) andthe precipitate washed twice with water (500 ml. and 300 ml.), and driedto constant weight over phosphorous pentoxide in vacuum. The slightlyyellowish substance weighs 378 g. (76.6%) and consists of approx. 85%N-methyl-3,5-diaeetamido-2,4,6- triiodobenzoic acid, admixed with about5% 3,5-diacetamido-2,4,6-triiodobenzoic acid and about 15%N,N-dimethyl-3,5-diacetamido-2,4,6-triiodobenzoic acid. 3 g. of thisproduct is extracted twice with pyridine-containing alcohol. Theundissolved pyridine salt is treated with diluted hydrochloric acid,washed and dried, whereby 56% chromatographically pure N methyl 3,5diacetamido- 2,4,6-triiodobenzoic acid is obtained. By processing of thealcoholic mother liquors the yield of this compound can be increased.

EXAMPLE 6B N-m'ethyl-3,5-diacetamid0-2,4,6-trii0dobenzoic acid3,5-diaoetamido-2,4,6-triiodobenzoic acid g.) is suspended in water (-10ml.), 5 N potassium hydroxide (4.3 eqv.) is added and the mixture cooledto about C. Dimethyl-sulphate (0.5 eqv.) dissolved in an equal volume ofacetone is added drop by drop while stirring. After the reaction mixturehas been stirred for about 1 hour hydrochloric acid (1:1) is added, withstirring to pH about 0.5. The precipitate is filtered, washed andsuspended moist in 4 parts of water, concentrated ammonia is added to pHabout 7 and the ammonium salt solution is isomerized at 90100 C. forabout half an hour whereafter additional ammonia is added to pH about 9followed by solid ammonium chloride (about 10% weight/volume) and thesolution stirred over night and the excess of 3,5-diacetamide-2,4,6-triiodobenzoic acid recovered as ammonium salt on the filter. Thefiltrate is precipitated by means of hydrochloric acid (1:1) at pH about0.5 and the N-methyl-3,5-diacetamido-2,4,fi-triiodobenzoic acidcollected on a filter, washed and dried.

EXAMPLE 7 Methyl N,N'-dimethyl-3,5-diacetamid0-2,4;6 .triiodobenzome 50g. of methyl 3,5-diacetamido-2,4,fi-triiodobenzoate is dissolved in amixture of 50 ml. 5 N potassium hydroxide and 200 ml. of water bycareful heating under mechanical stirring. At 4850 21.5 ml. ofdimethylsulphate is added under constant stirring, 12-16 drops perminute. After the solution has become neutral, it is heated for '5minutes to 55-65. The product is filtered ott, extracted hot for a fewminutes with '2 N potassium hydroxide, cooled, filtered, washed anddried, whereby 50.0 g. (94%) pureN,N-dimethyl-3,5-diacetamido-2,4,6-triiodobenzoic acid methyl ester isisolated.

EXAMPLE 8 N,N -dimethyl-3 ,5 -diacetam id0-2,4, 6 triiodobenzoic acid3,S-diacetamido-2,4;6-triiodobenzoic acid (10 g.) is sus pended in -10m1. of water and 5 N potassium hydroxide (6 eqv.) added and the mixturecooled to about 15 C. Dimethyl sulphate (1.4 eqv.) dissolved in an equalvolume of acetone is added drop by drop with stirring. The product isprecipitated by the addition of hydrochloric 10 acid, collected on afilter, resuspended moist in about 4 volumes of water and dissolved bythe addition of alkali to pH about 7. The solution is now isomerised byheating to 90-100" C. for about 1 hour, cooled and reprecipitated bymeans of hydrochloric acid, filtered, washed and dried in the ordinaryway, yielding about 10 g. of dryN,N-dimethyl-3,5-diacetamido-2,4,6-triiodobenzoic acid.

EXAMPLE 9 Propylation of 3,5-diacetamid0-2,4,6- triiodobenzoic acid 3,5-diacetamido-2,4,6-triiodobenzoic acid (5 g.; 8.2 mmol.) was suspendedin water (5 ml.), and brought into solution by means of the addition of5 N potassium hydroxide (6.5 ml.; about 4 eqv.). n-Propyl iodide (0.8ml.; 8.2 mmol.) dissolved in acetone (1 ml.) was added and the mixtureheated under reflux and mechanical stirring on the boiling water .bathfor about 1 hour. The temperature was then decreased to between 60 andC. and the .solution was stirred at this temperature for another hour.The mixture was then cooled to room temperature and acidified by meansof hydrochloric acid (1:1) .to pH about 0.5.. The precipitate wasfiltered, washed with water and dried yielding a product (4.8 g.; yield)having a M.P. 215 C. (decomp) and which by comparative chromatography ofunisomerised and isomerised samples indicated a mixture of about 50%starting material, 30% N-propyl-3,5-diacetamido-2,4,6- triiodobenzoicacid and about 20% of N,N'-dipropyl-3,5-diacetamido-Z,4,6-triiodobenzoic acid.

EXAMPLE 10 Propylation of methyl 3,5-diacetamido-2,4,6- triiodobenzoateMethyl 3,S-diacetamido-2,4,6-triiodobenzoate (5 g.; about 8 mmol.) wassuspended in water (5 ml.), and then brought into solution by means of 5N potassium hydroxide (6.5 ml.; 4 eqv.). Propyl iodide (0.78 ml.; 8.0mmol.) dissolved in acetone (1 ml.) was added. The mixture was heatedunder reflux and mechanical stirring on the boiling water bath for about1 hour. And then for a further hour at 60 80 C. A precipitation occurredduring heating and the precipitated methyl N,N-dimethyl- 3,5-diacetamido2,4,6-triiodobenzoate weighed 1.3 g. and melted at 220 C. (decomp.). Asample was converted to the corresponding acid by means of aminolysisand a chromatogramme showed it to be pure dipropyl compound.

The filtrate was acidified with concentratedhydrochloric acid-topH about0.5, and filtered, and washed by suspending it twice in 50 ml. each timeof 0.5-M sodium carbomate, and filtered a new. After final washing witha little water the methylN-propyl-3,S-diacetamido-2,4,6-triiodobenzoate' weighed dry 3.0 g. andmelted 'at 220 C. (decomp.). A sample of this product was converted tothe corresponding acid and chromatographed, the chromatogramme showingthat it consisted of the monopropyl compound with only traces ofstarting material and dipropyl compound present.

EXAMPLE 11 N,N-dimethyl-adip0yZ-bis- (3-carb0m'etlz0xy2,4,6-triiodaanilide) Adipoyl-bis-(3-carboxy-2,4,6-triiodoanilide) (29.8 g.)was dissolved in potassium hydroxide (60 ml.; 2.5 N) and dimethylsulphate (18 ml.) added with stirring in the course of 5 minutes. Thetemperature rose to 40 and the solution became cloudy. Successively morepotassium hydroxide (60 ml.; 5 N) and .dimethyl sulphate (72 ml.) wereadded in portions whereby the temperature rose further. After stirringfor about 1 hour the N,N-dimethyl-adipoyl-bis-(3 carbomethoxy 2,4,6triiodoanilide) (25 g.) was obtained after filtration, washing anddrying.

1 1 EXAMPLE 12 N ,N '-dimethyl-adi poy l-bis- (3 warmly-2,4,6-triiodoanilide) Adipoyl-bis-(3 carboxy-Z,4,6-triiodoanilide) (1.28 g.)Example 2:

React. React. Yield, Melting Example Compound Alkylating agent temp,time, Percent point,

0. hrs. C.

15 N-ethyl-3-acetamido-2,4,6- Ethyl iodide 65 2% 66 210-235triiodobenzoic acid.

16 N-n-propyl-3-acctamido-2,4,6 n-Propyl iodide 00 1 95 1 132-140triiodobenzoic acid.

17 N-n-butyl-3-acetamido-2,4,6- n-Butyl iodide 80-90 2 triiodobenzoicacid.

was dissolved in water (2 ml.) and acetone (1 ml.) and potassiumhydroxide (2 ml.; 5 N) added. Dimethyl sul- At these reactiontemperatures the conversion of the less stable isomers is not necessary.

phate (0.28 ml.; 1.4 eqv.) was added with stirring, where- The followingcompounds were prepared according to by the temperature rose from 21-31C. in the course of Example 3:

React. React. Yield, Melting Example Compound Alkylatlng agent temp,time, Percent point,

C. hrs. C.

18 5-amino-3-(N-ethy1aceta Ethyl iodide 65 1% 92 200-250midio)-2,4,6-triiodobenzoie aci 19 5-amino-3-(N-n-propyl-acetan-Propyliodide 90 1% 100 240-262d migo)-2,4,6-triiodobenzoic aei 205-amino-3-(N-n-butyl-acetan-Butyl iodide 00 2 80 155-160Inigo)-2,4,6-triiodobenzoie aei 21 5-amino-3-(N-n-pentyl-acetan-Pentyliodide 90 2 47 141 mligo)-2,4,6-triiodobenzoie ac 22 5-amino-3-(N-methylpropaf Dimethyl sulphate.-. l5 1 95 156-160 migo(-2,4,6-triiodobenzoicaci 23 5-amino3-(N-ethyl-propa Ethyl iodide 65 1% 95Inigo)-2,4,6-triiodobenzoio aei 24 5-amino-3(N-n-propyl-propan-Propyliodide 90 1% 75 migo)-2,4,6-triiodobenzoic ac 255-amino-3(N-methyl-butyra- Dimethyl sulphate..." 15 1 97 mi1(i1o)'-2,4,6-triiodobenzoic aci about seconds. After about 20 minutesthe reaction product was precipitated by means of strong hydrochloricacid (pH 0.5), filtered, washed and dried, whereby 1.15 g. ofchromatographically pure N,N'-dimethyl-adipoy1- vbis-(3-carboxy 2,4,6triiodoanilide) was obtained as a completely colourless product.

EXAMPLE l3 N,N'difi-hydroxyethyl) -3,5-diacetam hie-2,4,6-triiodobenzoic acid 3,5-diacetamido-2,4,6-triiodobenzoic acid (24 g.)was suspended in warm water (70 ml.) and dissolved by adding 10 N sodiumhydroxide (3O rnl.). Ethylenebromohydrin (16 ml.) was added to the stillwarm solution and left at room temperature over night.

The acid was then precipitated by means of concentrated hydrochloricacid to pH about 0.5, filtered, washed with water, dried andcrystallised from ethanol/ethylacetate.

Yield 17.5 g. (64%). Melting point l96-l97 C. Toxicity in mice LD :17.0g. acid/kg.

EXAMPLE 14 N-(fi-hydroxyethyl)3-acetamid0-2,4,6- triiodobenzoic acid Thecompound was prepared from 3-acetamido-2,4,6-

From these compounds the following diacyl-derivatives have beenprepared:

EXAMPLE 26 N,N'diethyl-3,5-diacetamido-2,4,6- triiodobenzoic acid3,5-diacetamido-2,4,6-triiodobenzoic acid (20 g.) was suspended in water(20 ml.) and 10 N sodium hydroxide 13 (22.8 ml.) added andthe mixtureheated to about 65 C. Ethyl iodide (8.1 ml.) was added with stirring.After 1% hours at 65 C. the solution was cooled and the productprecipitated by means of hydrochloric acid (1:1) to pH about 0.5,filtered, washed with water and dried.

Yield 18.3 g. (83.5%). Melting point 248-253" C.

EXAMPLE 27 N,N-dimethyl-3,5-diprpamid0-2,4,6-trii0d0benzoic acid Sodium3,5-dipropamido-2,4,6-triiodobenzoate (15 g.) dissolved in water (30ml.) was added 5 N sodium hydroxide (18 ml). Dimethyl sulphate (6.5 ml.)dissolved in acetone ml.) was added the cooled solutionwith stirring.After 1 hour the product was precipitated with concentrated hydrochloricacid, filtered, washed with water and dried.

Yield: g. (96%), melting point 230232 C.

EXAMPLE 28 N,N-dipr0pyl-3,5-dipr0pamid0-2,4,6-triiod0benz0ic acid Thiscompound was prepared as described in Example 27 by using propyl iodideas alkylating agent and the reaction temperature being 90 C.

Yield 53%, melting point 265-270 C.

EXAMPLE 29 N-carboxymethyl-fi-acetamido-Z,4,6-trii0d0benz0ic acid3-acetamido-2,4,6-triiodobenzoic acid (1 g.) was suspended in water (1ml.) and 5 N sodium hydroxide (3 ml.) added. Bromoacetic acid (1.01 g.)dissolved in water (1 ml.) was added drop by drop with stirring to thesolution which had been heated to 50 C. After about 30 min. at 5-'0-60C. the product was precipitated by means of concentrated hydrochloricacid to pH about 0.5, filtered, washed withwater and dried.

Yield 82%, melting point 255 C.

EXAMPLE 30 N ,N '-dicarb0xymethyl-3 ,5 -diacetamid0-2,4,6-zriiodobenzoic acid This compound was prepared from 3,5-diacetamido-2,4,6-triiodobenzoic acid as described in Example 29.

Yield: 26%, melting point 150-180 C.

EXAMPLE 31 3-(N-carboxymethylacetamido) -5-amin0-2,4,6- triiodobenzoicacid This compound was prepared from- 3-acetamido-5-amino-2,4,6-triiodobenzoic acid as described in Example 29.

Yield: 90%, melting point: 160-161 C.

EXAMPLE 32 N-methyl-2,4,6-trii0d0-/3-carboxypropanilide EXAMPLE 33N-ethyl-2,4,6-trii0d0-[i-carboxypropanilide The compound was prepared asdescribed in Example 32, using ethyl iodide as the alkylating agent.'The reaction temperature was 70 C.

Yield: 77%, melting point: 146-149 C.

EXAMPLE 34 N-n-propyl-2,4,6-trii0d0-,8-carboxypropanilide The compoundwas prepared as described in Example 32. Using 'n-propyl iodide as the.alkylating agent. The reaction temperature was 90 C.

Yield: %,.meltingpoint 167-178 C.

We claim:

1. A compound selected from the group consisting of a compound of theformula in which R is a member selected from the group consisting oflower carboxyalkyl, lower carbalkoxyalkyl and lower hydroxyalkyl, Z islower alkanoyl, Y is a member selected from the group consisting ofhydrogen, amino, lower alkanoylamido and and R is a member selected fromthe group consisting of hydrogen and lower alkyl; a compound of theformula 0 o 0 R O o o R I I I I f r Y III(CHz)4-ll Y I R R I I I inwhich Y, R and R have the same meaning as above; and nontoxic salts ofthe compounds of both of said formulas in which R is hydrogen.

2. N,N-di-(fi-hydroxyethyl) 3,5 diacetamido-2,4,6- triiodobenzoic acid.

3. N-(fl-hydroxyethyl) 3 acetarnido 2,4,6 triiodobenzoic acid. 7

4. A process for the preparation of a compound selected from the groupconsisting of a compound of the formula COOR in which R is a memberselected from the group consisting of lower carboxyalkyl, lowercarbalkoxyalkyl and lower hydroxyalkyl, Z is lower alkanoyl, Y is amember selected from the group consisting of hydrogen, amino, loweralkanoylamido and and R is a member selected from the group consistingof hydrogen and lower alkyl and a compound of the formula o o R 30 0 R I-I I- I 0 0 II U Y 1TIo(0H.)i I?T -Y R R I I I in which Y, R and R havethe same meaning as above, comprising reacting the correspondingcompound in which "15 1 0 R is hydrogen with a compound selected fromthegroup 2,776,241 1/57 Priewe 260471 consisting of lower haloalkanoicacids, lower alkyl esters 3,048,626 8/62 Wallingford 260-562 XR of lowerhaloalkanoic acids and lower alkylene halohy- FOREIGN PATENTS drins inthe presence of an aqueous alkaline medium.

5. The process of preparing N,N'-di(B-hydroxyethyl) 5 820,661 9/59 GmatBntam' 3,5-diacetamido-2,4,6-trii0dobenzoic acid, comprising re- 576,5075/59 Canadaacting 3,5 diacetamido 2,4,6 triiodobenzoic acid with 321,12112/02 ethylenebrornohydrin in the presence of an aqueous solu- OTHERREFERENCES of sodium hydroxlde' Migrdichian: Organic Synthesis, vol. II,(New York 10 References Cited by the Examiner 1957) 1440' UNITED STATESPATENTS LEON ZITVER, Primary Examiner.

2,060,851 11/36 Calcott et a1 260-584 DUVAL T. MCCUTCHEN, DANIEL D.HORWITZ, 2,611,786 9/52 Wallingford 260-471 Examiners.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA
 4. A PROCESS FOR THE PREPARATION OF A COMPOUND SELECTED FROMTHDE GROUP CONSISTING OF A COMPOUND OF THE FORMULA